Substituted 6-(1-pyrrolidine)quinolin-2(1H)-ones as Novel Selective Androgen Receptor Modulators

J Med Chem. 2007 Oct 18;50(21):5049-52. doi: 10.1021/jm070231h. Epub 2007 Sep 21.

Abstract

The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.

MeSH terms

  • Administration, Oral
  • Anabolic Agents / chemical synthesis*
  • Anabolic Agents / pharmacokinetics
  • Anabolic Agents / pharmacology
  • Androgen Receptor Antagonists*
  • Androgens*
  • Animals
  • Biological Availability
  • Bone Density Conservation Agents / chemical synthesis*
  • Bone Density Conservation Agents / pharmacokinetics
  • Bone Density Conservation Agents / pharmacology
  • Female
  • Humans
  • Hypogonadism / drug therapy
  • Hypogonadism / pathology
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Organ Size / drug effects
  • Osteoporosis, Postmenopausal / drug therapy
  • Prostate / drug effects
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology
  • Quinolones / chemical synthesis*
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 6-(2-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-4-trifluoromethylquinolin-2(1H)-one
  • Anabolic Agents
  • Androgen Receptor Antagonists
  • Androgens
  • Bone Density Conservation Agents
  • Pyrrolidines
  • Quinolines
  • Quinolones